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Live-attenuated vaccines are widely used for prevention and control of Infectious Bursal Disease (IBD) in poultry, yet differences in attenuation, replication and immunogenicity among vaccines remain incompletely characterised. This study comparatively evaluated three live-attenuated IBDV vaccines (Vaccine-A, Vaccine-B and Vaccine-C) using integrated molecular, pathobiological and immunological analyses. Molecular analysis using next-generation sequencing revealed that all vaccines possessed canonical attenuation-associated substitutions (253H, 279N and 284 T) in the VP2 hypervariable region, but differed in additional lineage- and virulence-associated residues. Vaccine-A retained several residues characteristic of very virulent IBDV (vvIBDV), including 222A, 242I, 256I, 294I and 299S, whereas Vaccines-B and -C displayed mixed classical and vvIBDV-associated profiles. Notably, Vaccine-C contained a vvIBDV-derived VP1 polymerase. These molecular differences corresponded to distinct in vivo phenotypes. Vaccine-C showed higher and more persistent vaccine-viral RNA levels in the bursa of Fabricius, with greater lymphoid depletion and lesion severity. In contrast Vaccine-A exhibited lower residual viral RNA levels and milder pathology. All vaccines induced homologous and cross-neutralising antibody responses, although response kinetics differed. Vaccine-A elicited earlier cross-neutralising responses, while Vaccine-C generated higher peak titres at later time points. Cytokine profiling showed stronger pro-inflammatory signals with Vaccine-C and higher early type-I interferon expression with Vaccine-A. Under selective pressure in DT-40 cells, Vaccine-A lost vvIBDV-associated residues, Vaccine-B accumulated substitutions including N279D, whereas Vaccine-C exhibited moderate VP2 variability. Overall, these findings suggest that vaccine molecular composition may influence viral replication, tissue pathology and immune responses, with Vaccine-A demonstrating a relatively favourable balance between safety and immunogenicity under the present experimental conditions.

In recent years, the zebrafish (Danio rerio) has become a prominent vertebrate model for toxicological and pharmacological research. Over 70% of its genome shares orthologous sequences with that of humans, establishing it as a genetically manipulable system that mirrors significant drug-target interactions and pathways associated with human diseases. While external fertilization and fast growth (organ function within 96-120 h) are made possible by transparent embryos and larvae, real-time, noninvasive monitoring of organogenesis and cellular processes is also made possible. Enable multi-well formats for high-throughput phenotypic screening. These characteristics, together with affordable housing expenses and adherence to the 3R ethical standards, make zebrafish an ethically and financially advantageous substitute for mammalian models. Its predictive value for developmental, neuro, and cardiotoxicity evaluations has been validated by comparative studies that show ≥ 80% concordance between zebrafish toxicity findings and mammalian data. Recent developments allow for exact dose-response modeling, metabolic profiling, and mechanistic dissection of oxidative stress, ER stress, inflammation, and apoptotic pathways by combining zebrafish tests with quantitative systems pharmacology. Additionally, zebrafish are being used more and more in environmental toxicology to examine the effects of pollutants on behaviors and neurodevelopment, bridging the gap between risk assessment for human health and the environment. The zebrafish model, when utilized in combination, provides significant experimental throughput and relevance for translation and accelerates safety pharmacology, toxicological mechanistic studies, and the process of drug development.

In randomized controlled trials with survival time as the primary endpoint, it can be difficult to evaluate treatment effects using hazard ratios, particularly when the proportional hazards (PH) assumption is violated. The difference in restricted mean survival time (RMST) up to a pre-specified time point, τ, is an alternative to the hazard ratio. However, the relative advantages of parametric (flexible parametric modeling [FPM]) and nonparametric approaches (direct integration of the Kaplan-Meier curve [DI], pseudo-observation [PO], and inverse probability of censoring weighting [IPCW]) for the estimation of RMST and its difference between groups are not clearly established. In this study, we performed comparative simulation studies to evaluate the performance of these methods for unadjusted and adjusted analyses in both PH and non-PH scenarios. For PO, IPCW, and FPM, we also considered a scenario where important covariates were adjusted via regression models. We obtained several key findings. For scenarios where the total number of events was >35, FPM tended to be unbiased, with higher power in PH scenarios. In non-PH scenarios, FPM exhibited slight bias with comparable power. For scenarios where the total number of events was ≤35, FPM showed unstable results. Among nonparametric methods, the bias and differences in power were negligible, except when the number of patients at risk at τ was ≤15; in this setting, IPCW showed conservative power and, under regression adjustment, a slight bias. These results provide a basis for the selection of methods to estimate RMST based on the expected prognosis.

The incidence of early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before the age of 50 years, has been increasing. The relationship between demographic, birth, and parental characteristics and risk of EOCRC has not been elucidated. This study included 1221 cases born and diagnosed with EOCRC at the age of 0 to 39 years in California during 1988 through 2021 and 61,050 frequency-matched controls based on birth year. Odds ratios (OR) and 95% CIs were estimated using multivariable logistic regression models. Based on multivariable analysis, males had 34% higher risk of EOCRC compared to females (OR = 1.34; 95% CI, 1.20-1.51), and Hispanic ethnicity was associated with 43% higher risk of EOCRC (OR for Hispanic versus non-Hispanic White = 1.34; 95% CI, 1.20-1.51). Having a foreign-born mother was associated with a lower risk of EOCRC (OR = 0.85; 95% CI, 0.73-0.97). Among females, every 500-g increase in birthweight was associated with 10% increase in EOCRC risk (OR = 1.10; 95% CI, 1.01-1.21) and having a father aged ≥35 years was associated with higher risk of EOCRC (OR = 1.56; 95% CI, 1.08-2.25). No other demographic, birth, and parental characteristic was significantly associated with risk of EOCRC. High birthweight, male sex, Hispanic ethnicity, and older paternal age are potential risk factors for EOCRC. Maternal birthplace, which is associated with diet, smoking patterns, other health-promoting characteristics, may be protective against EOCRC. These factors require future research for validation and evaluation of possible mechanisms.

There is limited evidence regarding the use of acute interventions and outcomes in patients with hematological malignancies presenting with acute ischemic stroke (AIS). In this study, we aimed to evaluate the outcomes of AIS in patients with hematological malignancies. Hospitalizations with primary diagnosis of AIS were identified from the Nationwide Readmissions Database 2016-2018. Logistic regression was used to compare differences in acute stroke interventions and clinical outcomes. Survival analysis was used to evaluate recurrent AIS after discharge. There were 1,347,150 hospitalizations due to AIS (mean ± SD age 70.3 ± 14.1 years, female 50.2%). Of these, 11,863 (0.9%) had a concurrent diagnosis of hematological malignancy. Patients with malignancy were less likely to receive intravenous thrombolysis (tPA) but not mechanical thrombectomy (MT). Among different hematological malignancies, patients with acute leukemia and Hodgkin lymphoma had a higher likelihood of in-hospital mortality, as compared to patients without malignancy. However, among patients treated with tPA or MT, clinical outcomes were comparable between the groups. Risk of readmission due to recurrent ischemic stroke was similar between patients with and without malignancy (hazards ratio: 1.0, 95% CI: 0.9-1.1). Patients with hematological malignancies are less likely to receive tPA but not MT; however, their use is not associated with increased harm. Patients with acute leukemias and Hodgkin lymphoma have an increased risk of in-hospital mortality, but the use of acute reperfusion therapies appears to attenuate this excess risk. Early risk of stroke recurrence is not different in patients with and without hematological malignancies.

Copy number variation (CNV), as a major type of DNA structural variations (SVs), plays a key role in causing human diseases and contributing to genetic diversity. Accurate identification of CNVs is significant for disease mechanism analysis, personalized diagnosis and treatment, and drug development. Although next-generation sequencing (NGS) technology has greatly promoted the development of CNV detection methods, the existing methods generally have problems such as high false positives and inaccurate boundaries. Therefore, a new method is proposed for detecting CNVs in a single sample of NGS data, called CNV-ECOD. The method first employs the empirical-cumulative-distribution-based outlier detection (ECOD) algorithm to identify abnormal signals of read depth (RD) for preliminary detection of CNVs. To correct false positives and refine CNV boundaries further, it integrates paired-end mapping (PEM) and split read (SR) strategies. The integration of the RD-PEM-SR hierarchical progressive framework and the anomaly scoring mechanism based on ECOD can effectively improve the accuracy of CNV detection. Comparing our approach to four peer methods, simulation results demonstrate that it achieves the best balance between precision and sensitivity. Also, the proposed method has the best F1-scores and the highest overlap density scores (ODSs) in real-sample experiments. Therefore, CNV-ECOD is expected to develop into an efficient and robust CNV detection tool.

Duchenne muscular dystrophy (DMD) is an X-linked recessive condition that is characterized by muscle deterioration, loss of functional abilities, and shortened lifespan. There is growing evidence of skeletal muscle mitochondrial impairments in DMD, and 31phosphorous magnetic resonance spectroscopy (31P-MRS) provides a noninvasive marker of functional oxidative capacity of muscle. Therefore, the purpose of this study was to examine 31P-MRS indices of energetic status and oxidative capacity in DMD and correlate with clinical functional measures. In this study, we evaluated ambulatory participants with DMD (n&#x2009;=&#x2009;21, 8.7&#x2009;&#xb1;&#x2009;1.9&#x2009;years) and unaffected age-matched controls (n&#x2009;=&#x2009;20, 9.0&#x2009;&#xb1;&#x2009;2.8&#x2009;years) using a 3T MR system. 31P-MRS was used to measure relative changes in high-energy phosphates and muscle pH of the anterior compartment of the lower leg during and following isometric dorsiflexion muscle contractions (120&#x2009;s rest, 60&#x2009;s of contractions at 0.5&#x2009;Hz, and 420&#x2009;s recovery). Data were analyzed with jMRUI (v7.0), and a mono-exponential model was used to estimate the time constant (tau) of PCr recovery (PCr&#x3c4;). We observed that relative concentrations of inorganic phosphate to phosphocreatine (Pi/PCr) and phosphodiesters to ATP (PDE/ATP) were elevated (p&#x2009;<&#x2009;0.05) in DMD compared to controls, and the PCr&#x3c4; recovery was slower (p&#x2009;<&#x2009;0.01) in DMD than controls. PCr&#x3c4; recovery was correlated with the distance covered in the 6-min walk test (6MWT) (&#x3c1;&#x2009;=&#x2009;-0.61, p&#x2009;<&#x2009;0.01) and other timed functional measures (&#x3c1;&#x2009;=&#x2009;0.54-0.67, p&#x2009;<&#x2009;0.05). The findings from this study demonstrated that energetic status is altered and PCr recovery time is impaired in ambulatory boys with DMD indicating reduced oxidative capacity compared to unaffected controls. Overall, these findings support the use of 31P-MRS as a valuable noninvasive tool to evaluate skeletal muscle energetics and mitochondrial function in individuals with DMD.

This study estimated the cost-effectiveness of sacituzumab tirumotecan (Sac-TMT) versus pemetrexed-platinum chemotherapy as second-line therapy for advanced EGFR-mutated non-small cell lung cancer (NSCLC) in China. A partitioned survival model based on the OptiTROP-Lung04 trial was developed from the Chinese healthcare perspective. The incremental cost-effectiveness ratio (ICER) was compared with a willingness-to-pay (WTP) threshold of $26,889.37/QALY. One-way, two-way, and probabilistic sensitivity analyses, together with scenario analyses, tested the robustness of the findings. The base-case analysis results showed that over 10&#x2009;years, Sac-TMT gained 0.86 additional QALYs at an incremental cost of $64,255.79, yielding an ICER of $75,704.42/QALY, exceeding the WTP threshold. Key drivers were patient body weight, the per-unit cost of Sac-TMT (180&#x2009;mg), and the health utility value for the progressive disease state. The probability of Sac-TMT being cost-effective at the WTP threshold of $26,889.37/QALY was 0%. Patient assistance program reduced the ICER to $46,354.36/QALY. A price reduction exceeding 73.81% would bring the ICER below the WTP threshold. At current prices, Sac-TMT is not cost-effective as second-line therapy for advanced EGFR-mutated NSCLC in China.

Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of peptic ulcers. Tegoprazan, a novel potassium-competitive acid blocker, provides rapid and potent inhibition of acid production. This study evaluated whether tegoprazan 25 mg is non-inferior to lansoprazole 15 mg in preventing NSAID-induced peptic ulcer. In this double-blind, randomized, active-controlled, multicenter phase III trial, patients requiring NSAIDs for up to 24 weeks were randomized (1:1) to the tegoprazan or the lansoprazole group. The primary endpoint was the incidence of peptic ulcer at week 24 in the per-protocol population. Secondary endpoints were NSAID-induced gastrointestinal symptom-free rates. Safety outcomes included adverse drug reactions (ADRs) and serious adverse events (SAEs). A total of 392 patients were randomized, and 269 patients were analyzed in the perprotocol set. Tegoprazan was non-inferior to lansoprazole for the prevention of gastroduodenal ulcers (p=0.0004). The heartburn-free rate at week 12 was higher in the tegoprazan group (p=0.0421), while other symptom-free rates did not differ significantly. In terms of safety, ADR and SAE rates were comparable and not significantly different. Tegoprazan was non-inferior to lansoprazole in preventing NSAID-induced peptic ulcers with excellent tolerance. Tegoprazan represents a clinically effective alternative gastroprotective therapy (ClinicalTrials.gov identifier NCT04840550).

In Japan, liver transplantation (LT) for hepatocellular carcinoma (HCC) is restricted to patients with decompensated cirrhosis. We investigated the clinical course, prognosis, and medical expenditure of patients with Child-Pugh class A (CP-A) HCC initially within the Japan criteria, including changes in oncological eligibility for LT during follow-up. We retrospectively analyzed patients with HCC treated at Kanazawa University Hospital between 2011 and 2021. After applying the age criterion (<&#xa0;70&#xa0;years), 134 patients with CP-A HCC, 45 with CP-B HCC, and 6 LT recipients were included. Survival and cumulative HCC-related medical expenditures were compared. A transplantable period was defined as the interval during which both hepatic reserve and tumor burden met LT eligibility. LT achieved the most favorable prognosis, with a 5-year overall survival rate of 83.3%. Among patients with CP-A HCC, progression beyond the Japan criteria was associated with markedly reduced survival, approaching that observed in CP-B disease. Of 53 patients who progressed beyond the Japan criteria, only 12 (22.6%) retained a transplantable period (median, 10.6&#xa0;months). Early recurrence and a FIB-4 index >&#xa0;5 were independently associated with poor prognosis. The cost per treatment life-year did not differ significantly between LT recipients and certain CP-A HCC subgroups. Many patients with CP-A HCC initially within the Japan criteria lost oncological eligibility for LT before hepatic decompensation. Further studies are warranted to determine whether a subset of patients with compensated cirrhosis may benefit from LT and to inform future discussions regarding the potential expansion of LT indications.

Resilience to the interaction of multiple stress factors of drought, wildfire, and canker disease has been little studied. During the 2012 to 2016 megadrought in California, black walnut trees were observed to resprout from the base due to water stress-induced dieback. After monitoring plants for a year, wildfire burned all the plants at two&#xa0;of our study sites, which was followed by vegetative resprouting. Plants also expressed symptoms of canker disease. We thus had an opportunity to assess the impacts of water stress, wildfire, growth form, and canker disease on plant performance. Water potentials and photosynthetic rates of drought-induced resprouts were monitored and compared to nearby adults that had not experienced drought-induced dieback, both inland (San Dimas, California) and at coastal exposures (Malibu, CA). We monitored the recovery of adults and drought-induced resprouts from 2017 to 2019, including fire-induced resprouts at coastal exposures following a 2018 wildfire. In addition, stem canker number and canker length were compared among irrigated and non-irrigated growth forms, including drought-induced resprouts, coppice-induced resprouts, adults, and resprouting adults. Drought-induced resprouts displayed higher water potentials and photosynthetic rates than adults, especially during dry periods, but had lower (more negative) values than fire-induced resprouts. Non-irrigated walnut trees displayed greater canker initiation and canker elongation rates than irrigated trees, with irrigated coppice-induced resprouts showing the least canker development. Resprouting can temporarily relieve water stress, but xylem water stress and canker disease agents feed off one another. Repeat stresses of drought, fire and disease compound to reduce the resilience of individuals and populations of walnut.

Citrus peels have traditionally been used for their anti-inflammatory properties. Their bioactive compounds can modulate neutrophil activation and reduce ROS production, both of which play key roles in the development of many chronic inflammatory diseases. The present study aimed to investigate the anti-inflammatory potential of an orange peel aqueous extract (OPE) and its major flavonoid, hesperidin (HSP), using integrated in vitro, in vivo, and in silico approaches. The anti-inflammatory activities of OPE and HSP were first assessed in isolated human neutrophils through degranulation and total ROS production assays. In vivo effects were evaluated in male Wistar rats using xylene-induced ear edema and &#x3bb;-carrageenan-induced peritonitis models. In silico molecular docking analyses were performed to predict the interactions of hesperidin with key inflammatory targets. In vitro, OPE and HSP significantly inhibited ROS production in neutrophils stimulated with PMA and fMLF and markedly reduced neutrophil degranulation. In vivo, pretreatment with OPE or HSP resulted in a substantial decrease in ear edema and neutrophil infiltration in peritoneal exudates, with comparable effects to those of aspirin. Docking results showed strong predicted binding affinities of hesperidin for NADPH oxidase subunits, cyclooxygenases-1 and -2, p38 MAPK, and NF-&#x3ba;B. Collectively, these findings demonstrate that OPE and HSP exhibit potent anti-inflammatory effects via multiple complementary mechanisms, supporting the valorization of citrus by-products as nutritionally relevant functional ingredients with potential applications in the dietary management of inflammation-related disorders.

The Latine population is at least two times more likely to be food insecure compared to the non-Hispanic white population. Challenges in accessing sufficient, culturally preferred, and healthy foods, particularly for those in rural areas, include limited financial resources and transportation difficulties. Additionally, this population commonly has low enrollment in food assistance programs, an effective method in reducing food insecurity (FI). Obesity, diabetes, cardiovascular diseases (CVD), and depression are frequently associated with FI; the Latine population carries a disproportionately high burden or risk of these diseases. We aimed to understand the prevalence of FI, FI as a predictor and outcome variable, and health conditions associated with FI among the Latine population in rural, western North Carolina. We conducted a cross-sectional survey in community settings using purposive sampling. Data were analyzed using descriptive statistics, bivariate analysis, and multivariable binary logistic regressions. Among 193 participants, 47% reported FI. Those identifying as food insecure were more likely to report a household income under $35,000 (OR 5.49, 95% CI: 1.37, 22.06), low educational attainment (OR 3.85, 95% CI: 1.23, 12.04), and being unmarried (OR 3.53, 95% CI: 1.01, 12.20). When modeled as a predictor, FI was associated with higher odds of reporting symptoms of CVD (OR 3.95, 95% CI: 1.43, 12.14) and depression (OR 5.01, 95% CI: 1.45, 21.52). Our study demonstrates a high prevalence of FI and significant relationships between FI and a myriad of variables in a region of rural, western NC and contributes to a dearth of literature about the experience of FI among the Latine population. Understanding the predictors of FI in this context can better support efforts to increase food security among this population.

The aim of this in vitro study was to evaluate the influence of various adhesive applicators on the microshear bond strength (&#xb5;SBS) of flowable resin composite to dentin. Forty-two extracted molars were prepared as disks and divided into two groups. In the first group, GLUMA Bond Universal (Heraeus Kulzer GmbH) was applied to the tooth surface for 20 seconds using a bristle brush, while in the second group, the same adhesive was applied by the same operator using a microbrush. Photopolymerization was performed for 10 seconds using a Valo light-curing unit (Ultradent Products Inc.). Microcylindrical silicone tubes (2 mm long, 0.8 mm inner diameter) were used as molds on the bonded dentin surfaces, and Charisma Bulk Flow ONE resin composite (Heraeus Kulzer GmbH) was injected and cured for 20 seconds. Both groups underwent a &#xb5;SBS test, and the failure modes were examined microscopically. Student t-test compared the failure stress between the groups (p < 0.05). The bristle brush group had the highest mean stress at failure (49.09 &#xb1; 8.76 MPa) compared to the microbrush group (37.20 &#xb1; 6.77 MPa), which also had the highest percentage of adhesive failure (95.24%). The choice of adhesive applicator plays a significant role in determining the &#xb5;SBS of flowable resin composite to dentin. It is advisable to use a bristle brush applicator when applying adhesive.

Surgical resection remains the primary curative approach for malignant liver tumors and liver regeneration is essential for patient recovery following major hepatic resection. While its molecular and cellular mechanisms have been extensively studied, the in&#xa0;vivo metabolic dynamics underlying early regeneration remain incompletely characterized. Hyperpolarized [1-13C]pyruvate MRI (HP-MRI) offers a unique, noninvasive method to assess real-time metabolic fluxes in regenerating liver tissue. Twelve male Wistar rats were randomized to either 70% partial hepatectomy (PH; n&#x2009;=&#x2009;6) or nonsurgical controls (n&#x2009;=&#x2009;6). On postoperative day 1, all animals underwent HP-MRI and multiparametric proton MRI. Metabolic fluxes were quantified using area-under-the-curve ratios for lactate-to-pyruvate (L/P), alanine-to-pyruvate (A/P), and lactate-to-alanine (L/A). The PH group showed significantly higher L/P (0.267 [95% CI: 0.225-0.310] vs. 0.168 [95% CI: 0.135-0.200]; p&#x2009;<&#x2009;0.001) and A/P (0.236 [95% CI: 0.153-0.319] vs. 0.150 [95% CI: 0.128-0.172]; p&#x2009;=&#x2009;0.028) ratios compared to controls, indicating increased exchange of pyruvate to lactate and alanine. L/A ratios remained unchanged. These findings were supported by elevated biochemical markers of hepatic injury and changes in quantitative MRI parameters, including reduced ADC and IVIM flow fraction. HP-MRI revealed increased glycolytic and transaminase activity during early liver regeneration, consistent with the metabolic demands of hepatocyte proliferation. These results demonstrate the feasibility of HP-MRI for noninvasive metabolic assessment of liver regeneration in&#xa0;vivo and additionally provide insights into early regenerative metabolism. This suggests HP-MRI as a promising tool for assessing postoperative recovery in patients undergoing major hepatectomy.